Aurora Kinase A Inhibitors
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 4 1059
3.26 (t, J ) 4.9 Hz, 4H), 2.56 (t, J ) 4.9 Hz, 4H), 2.38 (s, 3H),
2.34 (s, 3H), 1.35 (t, J ) 7.2 Hz, 3H). LCMS-ESI (m/z): [M + 1]+
371.2.
(E)-5-(2-(4-Methoxybenzylidene)hydrazinyl)-3-methyl-N-
phenethyl-1H-pyrazole-4-carboxamide (12c). Compound 12c was
prepared from 10 and phenylethylamine in 23% yield by the same
procedure as described for 12a. 1H NMR (CDCl3): δ 9.87 (s, 1H),
7.75 (s, 1H), 7.55 (d, J ) 8.7 Hz, 2H), 7.36-7.31 (m, 2H),
7.27-7.22 (m, 3H), 6.90 (d, J ) 9.0 Hz, 2H), 5.58 (br, 1H), 3.83
(s, 3H), 3.68 (q, J ) 6.9 Hz, 2H), 2.90 (t, J ) 6.9 Hz, 2H), 2.17
(s, 3H). HRMS (M+): calcd for C21H23N5O2, 377.1852; found,
377.1832.
(E)-5-(2-(4-Methoxybenzylidene)hydrazinyl)-3-methyl-N-(3-
phenylpropyl)-1H-pyrazole-4-carboxamide (12d). Compound 12d
was prepared from 10 and phenylpropylamine in 24% yield by the
same procedure as described for 12a. 1H NMR (CDCl3): δ 9.85 (s,
1H), 7.74 (s, 1H), 7.54 (d, J ) 8.7 Hz, 2H), 7.31-7.24 (m, 2H),
7.21-7.15 (m, 3H), 6.89 (d, J ) 9.0 Hz, 2H), 5.66 (br, 1H), 3.82
(s, 3H), 3.44 (q, J ) 7.2 Hz, 2H), 2.71 (t, J ) 7.7 Hz, 2H), 2.36
(s, 3H), 1.94 (p, J ) 7.2 Hz, 2H). HRMS (M+): calcd for
C22H25N5O2, 391.2008; found, 391.1986.
(E)-5-(2-(4-Methoxybenzylidene)hydrazinyl)-3-methyl-N-
phenyl-1H-pyrazole-4-carboxamide (12e). Compound 12e was
prepared from 10 and aniline in 15% yield by the same procedure
as described for 12a. 1H NMR (CDCl3): δ 7.77 (s, 1H), 7.56-7.52
(m, 5H), 7.38-7.33 (m, 2H), 7.16-7.10 (m, 1H), 6.89 (d, J ) 7.2
Hz, 2H), 3.82 (s, 3H), 2.56 (s, 3H). 13C NMR (CDCl3): δ 163.3,
161.0, 150.5, 145.5, 142.9, 137.9, 129.3, 128.5, 126.8, 124.4, 120.6,
114.5, 95.5, 55.6, 15.1. HRMS (M+): calcd for C19H19N5O2,
349.1539; found, 349.1522.
(E)-5-(2-(4-Methoxybenzylidene)hydrazinyl)-N,3-dimethyl-N-
phenyl-1H-pyrazole-4-carboxamide (12f). Compound 12f was
prepared from 10 and N-methylaniline in 17% yield by the same
procedure as described for 12a. 1H NMR (CDCl3): δ 9.20 (s, 1H),
7.76 (s, 1H), 7.57 (d, J ) 8.7 Hz, 2H), 7.31-7.26 (m, 2H),
7.18-7.13 (m, 3H), 6.91 (d, J ) 9.0 Hz, 2H), 3.84 (s, 3H), 3.46
(s, 3H), 1.46 (s, 3H). LCMS-ESI (m/z): [M + 1]+ 364.2, [M +
Na]+ 386.2.
(E)-Ethyl 5-(2-((1H-Indol-5-yl)methylene)hydrazinyl)-3-methyl-1H-
pyrazole-4-carboxylate (8g). Compound 8g was prepared from
7 and indole-5-carboxaldehyde in 47% yield by the same procedure
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as described for 8a. H NMR (CDCl3): δ 9.22 (s, 1H), 8.84 (s,
1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.53 (d, J ) 8.7 Hz, 1H). 7.30 (d,
J ) 8.7 Hz, 1H). 7.17 (s, 1H), 7.00 (br, 1H), 6.50 (s, 1H), 4.29 (q,
J ) 7.1 Hz, 2H), 2.38 (s, 3H), 1.34 (t, J ) 7.1 Hz, 3H). LCMS-
ESI (m/z): [M + 1]+ 312.2, [2M + Na]+ 645.3.
(E)-Ethyl 5-(2-((1H-Indol-4-yl)methylene)hydrazinyl)-3-methyl-1H-
pyrazole-4-carboxylate (8h). Compound 8h was prepared from
7 and indole-4-carboxaldehyde in 73% yield by the same procedure
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as described for 8a. H NMR (DMSO-d6): δ 11.26 (s, 1H), 9.86
(bs, 1H), 8.57 (s, 1H), 7.37-7.43 (m, 3H), 7.10-7.14 (m, 2H),
4.24 (q, J ) 5.3 Hz, 2H), 2.30 (s, 3H), 1.31 (t, J ) 5.3 Hz, 3H).
LCMS-ESI (m/z): [M + 1]+ 312.1, [2M + Na]+ 645.3.
(E)-Ethyl 5-(2-(1-(4-Methoxyphenyl)ethylidene)hydrazinyl)-
3-methyl-1H-pyrazole-4-carboxylate. (8i). Compound 8i was
prepared from 7 and 4′-methoxyacetophenone in 61% yield by the
1
same procedure as described for 8a. H NMR (CDCl3): δ 9.14 (s,
1H), 7.66 (d, J ) 8.7, 2H), 6.87 (d, J ) 8.7, 2H), 4.30 (q, J ) 6.9
Hz, 2H), 3.82 (s, 3H), 2.39 (s, 3H), 2.24 (s, 3H), 1.38 (t, J ) 7.2
Hz, 3H). LCMS-ESI (m/z): [M + 1]+ 317.1.
(E)-5-(2-(4-Methoxybenzylidene)hydrazinyl)-3-methyl-1H-
pyrazole-4-carboxylic Acid (10). To a solution of 7 (1.84 g,
10.0 mmol) in 20 mL of water, a solution of aqueous NaOH (0.8
g, 20 mmol, in 20 mL of water) was added, and the reaction mixture
was heated at 90 °C for 2 h. The reaction mixture was cooled on
an ice bath and neutralized to pH ∼7.0 by adding dropwise 2 N
HCl. A solution of p-anisaldehyde (2.04 g, 15.0 mmol) in EtOAc
(10 mL) was added to the aqueous reaction mixture and the reaction
mixture heated to 90 °C for 1 h. A yellow-white precipitate of the
product had started floating by this time. After the reaction mixture
was cooled to room temperature, it was filtered, and the solid
product obtained was suspended in EtOAc (10 mL), sonicated, and
then filtered. Sonication with EtOAc and filtration was carried out
two more times to remove impurities. The residue was dried under
vacuum to give pure off-white amorphous powder of 10 (1.51 g,
(E)-N-Benzyl-5-(2-(4-methoxybenzylidene)hydrazinyl)-N,3-
dimethyl-1H-pyrazole-4-carboxamide (12g). Compound 12g was
prepared from 10 and N-methylbenzylamine in 25% yield by the
same procedure as described for 12a. 1H NMR (CDCl3): δ 8.94 (s,
1H), 7.72 (s, 1H), 7.49 (d, J ) 8.4 Hz, 2H), 7.20-7.33 (m, 5H),
6.83 (d, J ) 8.4 Hz, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 2.92 (s, 3H),
2.24 (s, 3H). LCMS-ESI (m/z): [M + 1]+ 378.2, [M + Na]+ 400.2.
(E)-5-(2-(4-Methoxybenzylidene)hydrazinyl)-3-methyl-N-(2-
(pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide (12h). Com-
pound 12h was prepared from 10 and 3-(2-aminoethyl)pyridine in
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55%). H NMR (DMSO-d6): δ12.14 (bs, 2H), 9.84 (s, 1H), 8.19
(s, 1H), 7.68 (d, J ) 8.4 Hz, 2H), 6.96 (d, J ) 8.4 Hz, 2H), 3.79
(s, 3H), 2.26 (s, 3H). 13C NMR (DMSO-d6): δ 165.4, 160.0, 149.9,
147.6, 142.0, 128.1, 127.7, 114.1, 92.2, 55.2, 13.8. LCMS-ESI (m/
z): [M + 1]+ 275.1, [M + Na]+ 297.1, [2M + Na]+ 571.2.
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23% yield by the same procedure as described for 12a. H NMR
(E)-Benzyl 5-(2-(4-Methoxybenzylidene)hydrazinyl)-3-methyl-1H-
pyrazole-4-carboxylate (12a). Compound 10 (0.055 g, 0.20 mmol),
N-hydroxybenzotriazole monohydrate (0.034 g, 0.22 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.042
g, 0.22 mmol) were dissolved in anhydrous DMF (4.0 mL) and
stirred for 1 h under nitrogen atmosphere at room temperature. Then
benzyl alcohol (0.3 mmol) was added and the reaction mixture was
stirred further for 24 h at room temperature. DMF was removed
under reduced pressure on a rotary evaporator, and the residue
obtained was subjected to preparative TLC by developing the plate
twice in a mixture of CH2Cl2/MeOH (96:4) to give 12a (0.019 g,
26%). 1H NMR (CDCl3): δ 9.23 (s, 1H), 7.72 (s, 1H), 7.57 (d, J )
8.7 Hz, 2H), 7.34-7.44 (m, 5H), 6.91 (d, J ) 8.7 Hz, 2H), 5.31 (s,
2H), 3.84 (s, 3H), 2.41 (s, 3H). 13C NMR (CDCl3): δ 164.9, 161.2,
150.6, 149.8, 143.1, 136.6, 128.9, 128.6, 128.4, 128.1, 126.7, 114.4,
92.4, 65.9, 55.6, 14.5. HRMS (M+): calcd for C20H20N4O3,
364.1535; found, 363.1539.
(E)-N-Benzyl-5-(2-(4-methoxybenzylidene)hydrazinyl)-
3-methyl-1H-pyrazole-4-carboxamide (12b). Compound 12b was
prepared from 10 and benzylamine in 26% yield by the same
procedure as described for 12a. 1H NMR (CDCl3): δ 9.85 (s, 1H),
7.74 (s, 1H), 7.54 (d, J ) 9.0 Hz, 2H), 7.38-7.28 (m, 5H), 6.88
(d, J ) 9.0 Hz, 2H), 6.03 (br, 1H), 4.61 (d, J ) 5.4 Hz, 2H), 3.82
(s, 3H), 2.41 (s, 3H). HRMS (M+): calcd for C20H21N5O2, 363.1695;
found, 363.1683.
(CDCl3): δ 9.80 (s, 1H), 8.50-8.52 (m, 2H), 7.76 (s, 1H),
7.52-7.59 (m, 3H), 7.23-7.28 (m, 1H), 6.90 (d, J ) 8.7 Hz, 2H),
5.68 (bs, 1H), 3.83 (s, 3H), 3.67 (q, J ) 6.9 Hz, 2H), 2.92 (t, J )
6.9 Hz, 2H), 2.27 (s, 3H). LCMS-ESI (m/z): [M + 1]+ 379.3.
(E)-N-(2-(1H-Imidazol-4-yl)ethyl)-5-(2-(4-methoxybenzylidene)-
hydrazinyl)-3-methyl-1H-pyrazole-4-carboxamide (12i). Com-
pound 12i was prepared from 10 and histamine in 15% yield by
the same procedure as described for 12a. 1H NMR (CDCl3): δ 10.16
(bs, 1H), 8.10 (s, 1H), 7.69 (d, J ) 8.7 Hz, 2H), 7.65 (s, 1H), 7.16
(bs, 1H), 6.93-6.98 (m, 3H), 3.83 (s, 3H), 3.60 (q, J ) 6.6 Hz,
2H), 2.83 (t, J ) 6.6 Hz, 2H), 2.40 (s, 3H). LCMS-ESI (m/z): [M
+ 1]+ 368.2, [M + Na]+ 390.1.
(E)-N-(2-(1H-Indol-3-yl)ethyl)-5-(2-(4-methoxybenzylidene)-
hydrazinyl)-3-methyl-1H-pyrazole-4-carboxamide (12j). Com-
pound 12j was prepared from 10 and tryptamine in 20% yield by
the same procedure as described for 12a. 1H NMR (CDCl3): δ 9.87
(bs, 1H), 8.47 (s, 1H), 7.61-7.62 (m, 2H), 7.48 (d, J ) 8.7 Hz,
2H), 7.38 (d, J ) 7.8 Hz, 1H), 7.09-7.23 (m, 2H), 7.05 (d, J )
1.8 Hz, 1H), 6.84 (d, J ) 8.7 Hz, 2H), 5.76 (t, J ) 4.7 Hz, 1H),
3.70-3.79 (m, 5H), 3.06 (t, J ) 6.5 Hz, 2H), 2.05 (s, 3H). LCMS-
ESI (m/z): [M + 1]+ 417.2, [M + Na]+ 439.2.
(E)-N-(4-Methoxybenzyl)-5-(2-(4-methoxybenzylidene)-
hydrazinyl)-3-methyl-1H-pyrazole-4-carboxamide (12k). Com-
pound 12k was prepared from 10 and 4-methoxybenzylamine in
1
25% yield by the same procedure as described for 12a. H NMR